The present invention relates to controlled release preparations of (+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid (naproxen) and its pharmaceutically acceptable sodium salt (naproxen sodium). Specifically it relates to an oral dosage form comprising a matrix of naproxen or naproxen sodium in high molecular weight hydroxypropyl methylcellulose, which provides a release period suitable for daily dosing and exhibits good bioavailability. 2. Description of Related Art.
Naproxen and naproxen sodium are well known and widely used anti-inflammatory medications with analgesic and antipyretic properties. They are used for the relief of pain and inflammation generally, and for specific conditions such as arthritis and dysmenorrhea. Naproxen is available in 250 mg, 375 mg and 500 mg tablets and is generally administered in therapeutic doses of 500-1000 mg per day with dosing intervals of 8-12 hours. Naproxen sodium is available in 275 mg tablets and is generally administered in therapeutic doses of 550-1100 mg per day with dosing intervals of 8-12 hours.
Hydroxypropyl methylcelluloses are commercially available in various grades, under several tradenames, including Methocel E, F, J and K (all previously designated as Methocel HG) from The Dow Chemical Co., U.S.A., HPM from British Celanese, Ltd., England, and Metolose SH from Shin-Etsu, Ltd., Japan. The various grades available under a given tradename represent differences in methoxy and hydroxypropoxyl content as well as molecular weight and viscosity. Commercial designations of the various hydroxypropylmethylcellulose reflect their individual viscosity types and are based on the viscosities of 2% aqueous solutions at 20.degree. C. as determined according to the method described in the United States Pharmocopeia, Rev. 20. The viscosities range from 15 cps to 100,000 cps and represent number average molecular weights of from about 10,000 to over 150,000. In general, each of the various grades under a given tradename is a hydroxypropyl methylcellulose of a single viscosity type, e.g. 50 cps, 100 cps, 4000 cps, 15,000 cps, etc.
The area of controlled release pharmaceuticals is increasingly important in the formulation, manufacture and marketing of new pharmaceutical products. The technologies and corresponding products of this art are variously described as, among others, sustained release, controlled release, prolonged action, depot, repository, delayed action, retarded release, and timed release pharmaceuticals. In describing the present invention, the term "controlled release" is used to indicate that control is exercised over both the duration and profile of the in vivo drug release curve.
Controlled release drug dosage forms offer many advantages over conventional dosage forms for particular drugs. Of major importance both practically and therapeutically is the decrease in frequency of administration required to achieve the desired effect. A dosage form which is taken only once-a-day greatly improves patient compliance, and by extending the drug's activity through the night, permits the patient to sleep undisturbed until the morning. By enhancing the acceptability of a medication regime, patient compliance, and hence therapy, is improved.
Another important therapeutic advantage of some controlled release drug dosage forms is a reduction in the fluctuation of plasma drug concentrations. The pharmacologic basis for minimizing fluctuations in plasma drug levels derives from three basic principals. First, every drug has a therapeutic blood level that must be reached if the desired benefit is to be achieved from its use. When the condition being treated requires multiple doses over an extended period of time, the therapeutic blood level is the drug level which must be maintained to maximize the effectiveness of the medication. Second, most drugs have toxic blood levels that define the limit above which adverse reactions, or side effects, are experienced. Third, the drug concentration-response curve for most drugs is such that activity is approximately proportional to the logarithm of concentration. From these pharmacologic principles, a rationale for closely maintained plasma drug levels can be inferred. Several years of clinical testing has supported that rationale, and it is now widely agreed that where continuous drug treatment is desirable, therapy is optimized when the plasma drug concentration is maintained near the therapeutic level.
The mode of drug administration can influence the time course of therapeutic activity by affecting the profile of drug concentration in the blood. Conventional drug dosage forms are rapidly absorbed into the circulation and then metabolized; the blood level profile of the drug following a single conventional dose typically is defined by an initial high peak, followed by a rapid decline, the slope and duration of which depends upon such factors as the half-life of the drug. The initial high peak typically substantially exceeds the therapeutic plasma concentration range, and represents a large portion of the drug contained in the dosage form. After multiple periodic doses, a steady state mean plasma drug concentration is achieved, but the absolute level fluctuates in peaks and troughs above and below the mean level.
In contrast, controlled release drug dosage forms can extend the duration of therapeutic drug levels in the blood, and minimize or even avoid the initial spike in blood level concentration which is typical of conventional dosage forms. Additionally, while controlled release oral dosage forms do not inherently reduce the fluctuations in plasma drug concentrations, an opportunity to minimize these fluctuations arises from the fact that the rate of drug release is metered over a prolonged period of time.
A decrease in the fluctuation of plasma drug levels is achieved by balancing the in vivo release rate against the pharmacokinetics of the drug, i.e. absorption, distribution, metabolism and exretion, so that plasma drug level variation is minimized. The time course of change of drug concentration in the blood is the net result of the rate of delivery into, and the pharmacokinetic behavior of the drug in, the body.
Conventional dosage forms of naproxen and naproxen sodium are administered two to three times daily in order to maintain therapeutic blood levels, and to minimize the differential between peak and through blood levels during multiple dose therapeutic regimens. Peak to trough blood level ratios of about 2:1 are generally achieved with these regimens. In the interest of maximizing the therapeutic effectiveness of the drug, it is desirable to minimize as much as possible the ratio of peak to trough blood levels obtained during multiple dose therapy. Controlled release formulations generally permit less frequent dosing intervals to obtain acceptable peak to trough blood level ratios.
Many different types of controlled release oral dosage forms have been developed, but each has disadvantages which affect its suitability to a particular drug and therapeutic objective. Wide variations in the physicochemical and pharmacokinetic properties of different drugs impose such varied requirements on the design of controlled drug delivery formulations, that formulations which are suitable for one drug cannot generally be predictably applied to other drugs. A formulation which incorporates the drug in a soluble or erodible matrix is desirable due to its ease of manufacture, low incidence of lot to lot variability, and relatively low cost. The use of hydrophilic gums such as hydroxypropyl methylcellulose as sustained release matrix materials is known and has been demonstrated with a variety of active agents. However, no formulation of this type is known which is well suited for the controlled release of either naproxen or naproxen sodium.
Christenson and Dale (U.S. Pat. No. 3,065,143) disclosed the use of certain hydrophilic gums, including hydroxypropyl methylcellulose, as carrier base materials in the preparation of sustained release pharmaceutical tablets. The tablets consisted essentially of a mixture of a drug in combination with at least one-third part by weight of the hydrophilic gum. Examples 1 and 7 disclose the use of Methocel 60HG 4,000 cps (now known as Methocel E4M) which has a number average molecular weight of 93,000, as calculated from the data in the "Handbook of Methocel Cellulose Ether Products" (The Dow Chemical Co., 1974). Example 4 discloses the use of Methocel 90HG 4,000 cps, and Example 5 discloses the use of Methocel 90HG 15,000 cps, (now known as Methocel E4M and K15M respectively). The 4,000 cps and 15,000 cps viscosity grades indicate that the polymers have number average molecular weights of 89,000 and 124,000, respectively. Polymer to drug ratios given in the examples range from 1:2 to 10:1 and durations of sustained released of up to 12 hours in vitro are disclosed.
Schor and Nigalaye (U.S. Pat. No. 4,369,172, 1983) have disclosed the use of certain hydroxypropylmethylcelluloses for "prolonged release therapeutic compositions." In that case, the carrier base is low viscosity hydroxypropyl methylcellulose having a number average molecular weight below 50,000 and a hydroxy-propoxyl content of 9-12%. Specifically cited as examples corresponding to these criteria are Methocel E50 and Metolose 60SH50, which are 50 cps viscosity grade hydroxypropyl methylcellulose having number average molecular weight in the range of 23,000. Examples 1-4 describe tablets consisting essentially of about 57% by weight of one or the other of these two materials in combination with lithium carbonate. The tablets weighed about 700 mg and released the active agent for up to 14 hours in vitro. Examples 5-6 describe sustained release aspirin tablets in which the hydroxypropyl methylcellulose carrier base constitutes 16.5% of the total weight of the tablet. The tablets had an average weight of 787 mg and released 650 mg aspirin in vitro over a period of 6-8 hours. Further examples in U.S. Pat. No. 4,369.172 show tablets containing 16-20% by weight of the polymer and release of the active ingredient over 1-6 hours in vitro.
The Dow Chemical Company publishes a brochure entitled "Formulating Sustained Release Pharmaceutical Products with Methocel" (1982) which describes the various commercially available Methocel polymers, identifying their relative viscosities, rates of hydration and gel strength properties. The brochure also suggests criteria for formulating sustained release pharmaceutical products.
While the concept of utilizing hydroxypropylmethylcellulose in oral dosage forms to prolong the rate of release of drugs into the blood stream is known, and prolonged release of various active agents from such dosage forms has been demonstrated, the art available to formulate oral controlled release forms of naproxen and naproxen sodium has several disadvantages. First, it is apparent from the foregoing discussion of the relevant art that presently known sustained release tablet formulations rely on fairly high levels of hydroxypropyl methylcellulose to achieve adequate duration of drug release. The major problem with using any of these formulations is the additional bulk of the resulting tablet. In dry oral dosage forms, there is an approximate upper limit to the tablet bulk that will be tolerated by the patient. This limit varies from patient to patient, but can be as low as 650 mg. Thus, with drugs such as naproxen, whose therapeutic dosage range is 500-1200 mg/day, the additional tablet bulk which is created by inclusion of substantial amounts of matrix material will render the tablets unacceptable to many patients.
Furthermore, while the art demonstrates in vitro sustained drug release from several formulations using hydroxypropyl methylcellulose, the pharmacokinetics of in vivo drug release, absorption, distribution, metabolism and excretion impose more demanding requirements on the design of the controlled release tablet formulation than are apparent from in vitro testing. The present invention is directed to a new controlled release oral dosage formulation for naproxen or naproxen sodium which provides sustained therapeutic plasma drug levels for at least 24 hours, and requires a surprisingly small amount, about 4-9 weight percent, of hydroxypropyl methylcellulose. The low level of matrix material required by the present invention makes possible a once-daily naproxen or naproxen sodium dosage form without excessive bulk, having weight and size characteristics which make it well-adapted for practical and acceptable patient administration. Chronic once-daily administration of the controlled release tablets of the present invention also provides less fluctuation in plasma drug concentration than is provided by chronic twice-daily administration of conventional naproxen and naproxen sodium tablets. Additionally, the new formulation is advantageous from a manufacturing viewpoint since it requires the presence of only three elements: the naproxen or naproxen sodium, the hydroxypropylmethylcellulose, and a lubricating agent.